ABSTRACT: PROJECT 1 Project 1 is highly integrated with the other projects in this SRP proposal, and the primary goal is directly in line with the theme of the center, ?Identifying novel methods to reduce iAs exposure and elucidating mechanisms underlying iAs-induced metabolic dysfunction with a vision for disease prevention.? The project addresses the important public health issue of diabetes associated with environmental exposure to inorganic arsenic (iAs). It focuses on liver and pancreatic beta cell microRNAs (miRNAs) and transcription factors (TFs) as potential mechanisms of iAs-associated diabetes. The project co-leaders are Drs. Sethupathy and Styblo, experts in miRNA function and iAs toxicology. iAs has been highlighted as a diabetogen by the National Toxicology Program (NTP) 2012 review. Diabetes is a complex disorder that affects hundreds of millions of people worldwide, has no cure, is associated with numerous debilitating co-morbidities, and is a growing public health concern. Chronic exposure to iAs is a global problem as over 100 million people around the world (~13 million in US) drink water with unsafe levels of iAs and many more are exposed to iAs in food. Our prior research has shown that exposure to iAs is associated with increased prevalence of diabetes, and that impaired insulin secretion by pancreatic beta cells or impaired insulin signaling (insulin resistance) may underlie the diabetogenic effects of iAs. However, the mechanistic underpinnings of these effects are unknown. This proposal builds upon a productive collaboration between Drs. Sethupathy and Styblo and is based on robust preliminary data that points to miRNAs and TFs as strong candidate mechanistic links between iAs and diabetes. Over the last decade, specific miRNAs and TFs have independently emerged as markers of iAs exposure and as potential regulators of diabetes pathways. iAs exposure has been associated with significant changes in the levels of miRNAs and TFs in different tissues and cell lines. Importantly, some of these miRNAs and TFs have also been linked to diabetes in separate studies. Despite such intriguing findings, the relationship between iAs-exposure and miRNAs or TFs in diabetes has never been formally investigated. The goal of this study is to bridge this knowledge gap. Our central hypothesis is that specific miRNAs and TFs drive the diabetes phenotypes associated with iAs exposure, and that manipulation of these miRNAs and TFs will rescue these phenotypes. We will test this hypothesis through the use of in vitro cell-based systems, in vivo mouse models, and human samples. Given the potential for exposure to iAs and the public health issue of diabetes, understanding the complex relationships between environmental risk factors for diabetes is of critical importance.